Biphenyl compound selective agonists of gamma RAR receptors

ABSTRACT

Biphenyl compounds having the formula (I): 
     
       
         
         
             
             
         
       
     
     are useful for preventing/treating pathologies linked to a deficiency of the activation of the RAR gamma receptor, e.g., for treating a pathology linked to a cell differentiation and/or proliferation disorder, for treating acne, for treating psoriasis.

CROSS-REFERENCE TO COMPANION APPLICATION

Copending U.S. patent application Ser. No. ______ [Attorney Docket No. 1034227-000930], filed concurrently herewith, hereby expressly incorporated by reference and also assigned to the assignee hereof.

CROSS-REFERENCE TO PRIORITY/PCT APPLICATIONS

This application claims priority under 35 U.S.C. § 119 of FR 0512762, filed Dec. 15, 2005, and is a continuation of PCT/EP 2006/068975, filed Nov. 28, 2006, and designating the United States (published in the French language on Jun. 21, 2007, as WO 2007/068579 A1; the title and abstract were also published in English), each hereby expressly incorporated by reference in its entirety and each assigned to the assignee hereof.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to the therapeutic administration, in particular in the dermatology field, of novel biphenyl compounds substituted with an aromatic radical having selective activity for the gamma subtype of the RAR receptor family.

2. Description of Background and/or Related and/or Prior Art

A family of biphenyl compounds has been described in WO 99/10308. These compounds are described as having an application in the topical and systemic treatment of dermatological conditions linked to a keratinization disorder, and of opthalmological conditions in particular.

The activity of these compounds has in particular been demonstrated by means of tests for differentiation of mouse embryonic teratocarcinoma F9 cells and keratinocyte differentiation tests in humans.

On the other hand, this publication in no way makes any reference to a possible specific activity of the compounds with respect to the gamma subtype of RAR receptors.

Indeed, the gamma subtype of the RAR receptor family is largely predominant in the epidermis, where it is approximately 90% of the total receptors (“Retinoic acid receptors and binding proteins in human skin”, Elder J T, Astrom A, Pettersson U, Tavakkol A, Krust A, Kastner P, Chambon P, Voorhees J J: J. Invest Dermatol., 1992; 98 (6 Suppl): 36S-41 S; or “Retinoic acid receptor expression in human skin keratinocytes and dermal fibroblasts in vitro”, Redfern C P, Todd C., J. Cell Sci., 1992; 102 (Pt 1): 113-21), and it is indeed the interaction with this RAR gamma receptor which is responsible for the effectiveness of retinoids on the epidermis (“Retinoic acid receptor gamma mediates topical retinoid efficacy and irritation in animal models”, Chen S, Ostrowski J, Whiting G, Roalsvig T, Hammer L, Currier S J, Honeyman J, Kwasniewski B, Yu K L, Sterzycki R, et al., J. Invest Dermatol., 1995; 104 (5): 779-83).

RAR gamma receptors are therefore the sole target in the treatment of pathologies at the epidermal level, for instance for acne or psoriasis or any other skin pathology treated with retinoids.

Furthermore, certain side effects specific to RAR alpha or RAR beta can be avoided if compounds having a selective action on RAR gamma are used.

SUMMARY OF THE INVENTION

It has now surprisingly been shown that the compounds according to the invention have an extremely advantageous selective agonist activity for the gamma subtype of the RAR receptor family.

The compounds according to the invention, selective agonists of the RAR gamma subtype, thus make it possible to prevent and/or treat various dermatological pathologies or disorders, while at the same time decreasing the side effects normally caused by the action of the active agents on the RAR alpha and beta subtypes.

The present invention therefore features compounds having the following general formula:

in which R is a hydrogen or a hydroxyl radical, and also the salts of the compounds of formula (I).

The term “pharmaceutically acceptable salt” means in particular an alkali metal salt, or an alkaline-earth metal salt, or an organic amine salt.

According to a preferred embodiment, the compounds of formula (I) are selected from 4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid and 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid.

The present invention also features the formulation of at least one compound of formula (I), into pharmaceutical or cosmetic compositions useful in preventing and/or treating pathologies for which a selective agonist activity for the gamma subtype of the RAR receptor family is desired.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE of Drawing is a reaction scheme illustrating preparation of the compounds according to the present invention.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OF THE INVENTION

A general synthetic pathway for preparing the compounds of formula (I) is represented in the scheme shown in the FIGURE of Drawing.

The starting materials and/or the reactants employed are commercially available and/or can be prepared according to known methods in the literature.

According to another embodiment, the present invention also features a process for preparing the compounds of formula (I) described above, comprising the following steps:

i) coupling reaction, preferably of Suzuki reaction type, from the compound of formula 1 prepared, for example, as described in WO 99/10308:

and the compound of formula 2 prepared, for example, as described in WO 99/10308:

to produce the compound of formula 3

ii) reaction of the phenol function of the compound of formula 3 with triflic anhydride ((CF₃CO)₂O), according to methods known in the literature (see, for example, Kotsuki H. et al., Synthesis, 1990, (12), 1145-1147 or Prince P. et al., Synlett, 1991, (6), 405-406), to produce the compound of formula 4,

iii) reaction, of Stille coupling type, of the compound of formula 4 with allyl tri-n-butyl tin (CH₂═CH—CH₂—SnBu₃) according to methods known in the literature (see, for example, Tilley J. W. et al., J. Org. Chem., 1990, 55(3), 906 or Saa J. M. et al., J. Org. Chem., 1992, 57(2), 678-685), to produce the compound of formula 5,

iv) hydration of the allylic double bond of the compound of formula 5, for example by a conventional hydroboration reaction followed by oxidation, according to methods known in the literature (see, for example: Liotta R., Brown H. C., J. Org. Chem., 1977, 42, 28-36 or Luo F. T., Negishi E., J. Org. Chem., 1983, 48, 5144) or dihydroxylation of the allylic double bond of the compound of formula 5 according to methods known in the literature (see, for example: Corey E. J. et al., Tetrahedron Lett 1984, 25 (44), 5013, Sharpless K. B. et al., J. Am. Chem. Soc., 1976, 98 (7) 1986), to produce the compounds of formula 6, with, respectively, R═H and R═OH:

v) saponification of the ester function of the compound of formula 6, to produce the compound of formula (I) (compound 7 in the FIGURE of Drawing) in which R is a hydrogen or a hydroxyl radical.

Step i) may, for example, be carried out in the presence of potassium carbonate and of tetrakis(triphenylphosphine)palladium in a toluene solution.

Step ii) may, for example, be carried out in the presence of trifluoromethanesulfonic anhydride and of a base such as triethylamine in an aprotic solvent such as dichloromethane.

Step iii) may, for example, be carried out in the presence of a palladium catalyst such as, for example, bis(triphenylphosphine)palladium chloride (PdCl₂(PPh₃)₂) or else tris(dibenzylideneacetone)dipalladium (Pd₂(dba)₃) in a polar solvent such as, for example, dimethylformamide.

Step iv) may, for example, be carried out in the presence of catalytic osmium tetraoxide and of an oxidant such as, for example, N-methylmorpholine N-oxide. As indicated above, in this case, the reaction produces the compound 6 in which R is the hydroxyl radical.

Alternatively, step iv) may also be carried out in the presence of a borane such as, for example, 9-borabicyclo[3.3.1]nonane (9-BBN) followed by oxidation using, for example, aqueous hydrogen peroxide. In this case, the reaction produces the compound 6 in which R is hydrogen.

Step v) may, for example, be carried out in the presence of sodium hydroxide and of THF.

The present invention also features administration of the compounds of formula (I) as described above, as a medicament.

According to another embodiment, this invention features pharmaceutical or cosmetic compositions, comprising, formulated into a pharmaceutically or cosmetically acceptable carrier, at least one compound of formula (I).

The term “pharmaceutically or cosmetically acceptable carrier” means a carrier suitable for use in contact with human and animal cells, with no toxicity, irritation, undue allergic response, and the like, and proportional to a reasonable advantage/risk ratio.

The administration may be carried out topically, enterally or orally, parenterally or ocularly, whether regime or regimen. Among these routes of administration, topical administration is particularly preferred.

When administered topically, the pharmaceutical compositions according to the invention are more particularly useful in the treatment of the skin and mucous membranes and may be in liquid, pasty or solid form, and more particularly in the form of salves, creams, milks, ointments, powders, impregnated pads, syndets, solutions, gels, sprays, mousses, suspensions, sticks, shampoos or washing bases. Same may also be in the form of suspensions of lipid or polymeric vesicles or microspheres or nanospheres, or polymeric or gelled patches for controlled release.

The compounds are employed topically at a concentration generally of from 0.001% to 3% by weight, relative to the total weight of the composition.

For cosmetic applications, the compositions are preferably in the form of a cream, a milk, a lotion, a gel, lipid or polymeric vesicles or microspheres or nanospheres, a soap or a shampoo.

When administered enterally or orally, the compositions may be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, or suspensions of lipid or polymeric vesicles or microspheres or nanospheres for controlled release. When administered parenterally, the compositions may be in the form of solutions or suspensions for perfusion or for injection.

The compounds according to the invention are generally administered at a daily dose of approximately 0.01 mg/kg to 30 mg/kg of body weight, taken in 1 to 3 doses.

The compounds of the invention can be formulated, alone or as a mixture, into pharmaceutical compositions useful in the treatment and/or prevention of pathologies linked to a deficiency in the activation of the RAR gamma receptor.

This invention also features a method of therapeutic or cosmetic treatment, comprising the administration of a pharmaceutical or cosmetic composition comprising at least one compound of formula (I), said compound exercising a selective agonist activity for the RAR gamma receptor.

The pharmaceutical compositions may be more particularly useful in treating a pathology for which the treatment requires a selective agonist activity for the RAR gamma receptor, more particularly at the level of the epithelial tissues, the skin and the bones.

The compositions can in particular be administered for the treatment of a pathology linked to cell differentiation and/or proliferation disorders, in particular in the dermatology field.

More particularly, same are useful in the treatment of a pathology linked to a keratinization disorder.

The treatment of acne is thus envisioned, in particular common acne, comedone acne, polymorphic acne, nodulocystic acne, acne conglobata, senile acne, secondary acne such as solar acne, acne medicamentosa or occupational acne.

The pharmaceutical compositions comprising a compound of formula (I) are also useful in the treatment of other dermatological conditions linked to a keratinization disorder with an inflammatory and/or immunoallergic component, and in particular all forms of psoriasis, whether cutaneous, mucosal or ungula.

The compounds according to the invention can also be formulated into cosmetic compositions, for combating skin aging, whether for example photoinduced or chronological, or else for the treatment of skin with an acneic tendency of for combating the greasy appearance of the skin or the hair.

The pharmaceutical or cosmetic compositions are also useful to regulate skin pigmentations and to treat actinic keratoses.

In all the applications envisioned, said compound may be combined with another therapeutic agent that can be used in the treatment of a pathology linked to cell differentiation or proliferation disorders.

As therapeutic agents that can be included in the compositions according to the invention, exemplary are agents for modulating skin differentiation and/or proliferation and/or pigmentation, such as retinoic acid and its isomers, retinol and its esters, retinal, retinoides, estrogens, anti-bacterial agents, antibiotics, anti-parasitic agents, anti-fungal agents, steroidal or non-steroidal anti-inflammatory agents, anesthetics, anti-pruriginous agents, anti-viral agents, keratolytic agents, free-radical scavengers, anti-seborrheic agents, anti-dandruff agents, anti-acne agents, agents for combating hair loss, and vitamin C and its derivatives, with the proviso, as is indicated above, that the active agents be in solubilized form in the composition according to the invention.

In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative. In said examples to follow, all parts and percentages are given by weight, unless otherwise indicated.

In the examples hereinafter, the samples were analyzed by ¹H NMR, ¹³C NMR and HPLC/MS.

Example 1 Synthesis of 4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid

a) Preparation of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

10 g (31 mmol) of ethyl 3′-bromo-4′-hydroxybiphenyl-4-carboxylate (prepared according to EP-952,974), 8.7 g (37 mmol) of 6-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene)boronic acid (prepared according to EP-952,974) and 34 ml (74.6 mmol) of a 2M aqueous solution of potassium carbonate are placed in 200 ml of toluene, in a three-necked flask, and then 1.8 g (1.55 mmol) of tetrakis(triphenylphosphine)palladium are added under nitrogen. The reaction mixture is heated for 24 h at 110° C. After cooling, the reaction is stopped by adding 200 ml of water and then extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride and dried over magnesium sulfate. The solvents are evaporated off and the residue is then purified by silica gel chromatography (80/20 heptane/ethyl acetate).

8 g of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (yield=60%).

b) Preparation of ethyl 3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4′-trifluoromethanesulfonyloxybiphenyl-4-carboxylate

8.8 ml (63 mmol) of triethylamine are added, dropwise, in a three-necked flask under nitrogen, to 18 g (42 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in solution in 250 ml of dichloromethane. The reaction medium is cooled to around 0° C. and then 8.48 ml (50 mmol) of trifluoromethanesulfonic anhydride are added dropwise. The reaction medium is stirred for 3 h at 0° C., and is then hydrolyzed, washed with a solution of sodium bicarbonate and dried over magnesium sulfate. After evaporation of the solvents, the isolated product is purified by silica gel chromatography (heptane/ethyl acetate=95/5).

24 g of ethyl 3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4′-trifluoromethanesulfonyloxybiphenyl-4-carboxylate are obtained in the form of a white powder (yield=100%).

c) Preparation of ethyl 4′-allyl-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

6 g (10.7 mmol) of ethyl 3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4′-trifluoromethanesulfonyloxybiphenyl-4-carboxylate, 0.9 g (21 mmol) of lithium chloride, 1.12 g (1.6 mmol) of bis(triphenylphosphine)palladium dichloride, 30 ml of dimethylformamide and 3.98 ml (12.8 mmol) of allyl tri-n-butyl tin are introduced into a three-necked flask, under nitrogen in this order.

The reaction mixture is stirred for 12 h at 100° C. The reaction is hydrolyzed with a 1 N solution of hydrochloric acid and then extracted with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvents are evaporated off. The crude obtained in the form of an oil is purified by silica gel chromatography (heptane/ethyl acetate: =95/5).

6.1 g of ethyl 4′-allyl-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate are obtained in the form of a light yellow oil (yield=100%).

d) Preparation of ethyl 4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

0.5 g (1.1 mmol) of ethyl 4′-allyl-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate is introduced into 20 ml of tetrahydrofuran, in a three-necked flask under nitrogen. This solution is cooled to 0° C. and then 6.6 ml (3.3 mmol) of a 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran are added dropwise. After the addition is complete, the reaction medium is stirred until it returns to ambient temperature. It is stirred for a further one hour at this temperature, and then again cooled to around 0° C. 3.4 ml (3.4 mmol) of a 1 M solution of sodium hydroxide are added slowly to the reaction medium, and then 2.8 ml (27.6 mmol) of a 30% aqueous hydrogen peroxide solution are added dropwise. After the addition is complete, the reaction medium is stirred while allowing the temperature to return to ambient temperature. The medium is stirred for 12 h at this temperature, and is then hydrolyzed with a solution of ammonium chloride. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with water and then dried over magnesium sulfate. The solvents are evaporated off. The crude obtained is purified by silica gel chromatography (heptane/ethyl acetate: 95/5).

300 mg of ethyl 4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate are obtained in the form of a colorless oil (yield=58%).

e) Synthesis of 4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid

1 ml (1 mmol) of an aqueous solution of sodium hydroxide (1 M) is added to a solution of 300 mg (0.64 mmol) of ethyl 4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in 15 ml of tetrahydrofuran and 1 ml of ethanol. The reaction mixture is stirred for 14 h while heating at 50° C. After the reaction mixture has returned to ambient temperature, 2 ml (2 mmol) of a solution of hydrochloric acid (1 N) are added. The medium is extracted with ethyl acetate. The organic phase is washed with water, and then dried over magnesium sulfate. After evaporation of the solvents, the product obtained is purified by silica gel chromatography (heptane/ethyl acetate: =3/2).

230 mg of 4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid are obtained (white solid, Mp=203° C., yield=90%).

Example 2 Synthesis of 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid

a) Preparation of ethyl 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

2.84 g (6.3 mmol) of ethyl 4′-allyl-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate (prepared according to Example 1, step c)) are introduced, in a three-necked flask under nitrogen, into 15 ml of dichloromethane and then 1.0 g (7.5 mmol) of N-methylmorpholine N-oxide is added.

2.27 ml (0.18 mmol) of a solution of osmium tetraoxide at 2.5% by weight in isopropanol are added at ambient temperature. The reaction medium becomes dark yellow. It is stirred for 3 h at ambient temperature, and is then hydrolyzed and extracted with dichloromethane. The combined organic phases are washed with sodium thiosulfate and then dried over magnesium sulfate. After evaporation of the solvents, the product obtained is purified by silica gel chromatography (heptane/ethyl acetate=1/1).

1.92 g of ethyl 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate are obtained in the form of a beige oil (yield=63%).

b) Synthesis of 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid

1 ml (1 mmol) of an aqueous solution of sodium hydroxide (1 M) is added to a solution of 200 mg (0.41 mmol) of ethyl 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in 5 ml of tetrahydrofuran and 2 ml of ethanol. The reaction mixture is stirred for 48 h while heating at 50° C. After the reaction mixture has returned to ambient temperature, 2 ml (2 mmol) of a solution of hydrochloric acid (1 N) are added. The medium is extracted with ethyl acetate. The organic phase is washed with water, and then dried over magnesium sulfate. After evaporation of the solvents, the product obtained is purified by crystallization from a heptane/diethyl ether mixture. 180 mg of 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid are obtained (beige solid, Mp=145° C., yield=96%).

Example 3 Transactivation Test

Principle of the Test:

The activation of the receptors by an agonist (activator) in HeLa cells results in the expression of a reporter gene, luciferase, which, in the presence of a substrate, generates light. It is thus possible to measure the activation of the receptors by quantifying the luminescence produced after incubation of the cells in the presence of a reference antagonist. The activating products displace the antagonist from its site, thus allowing activation of the receptor. The activity is measured by quantifying the increase in the light produced. This measurement makes it possible to determine the activator activity of the compound that can be used in the invention.

In this study, a constant which is the affinity of the molecule for the receptor is determined. Since this value can fluctuate according to the basal activity and the expression of the receptor, it is designated apparent Kd (KdApp).

In order to determine this constant, “cross curves” of the test product (4′-(3′-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid and 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid), against a reference antagonist otherwise known as reference ligand, 4-(5,5-dimethyl-8-p-tolyl-5,6-dihydronaphthalen-2-ylethynyl)benzoic acid, are produced. The test product is used at 10 concentrations and the reference antagonist at 7 concentrations. In each well (of a 96-well plate), the cells are in contact with one concentration of the test product and one concentration of the reference antagonist.

Measurements are also carried out for the total agonist control, otherwise known as 100% control (4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)propenyl]benzoic acid), and the inverse agonist control, otherwise known as 0% control (4-{(E)-3-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)]-3-oxopropenyl}benzoic acid).

These cross curves make it possible to determine the AC50 values (concentration at which 50% activation of the receptor is observed) of the reference ligand at various concentrations of test product. These AC50 values are used to calculate the Schild regression by plotting a straight line corresponding to the Schild equation (“Quantitation in receptor pharmacology” Terry P. Kenakin, Receptors and Channels, 2001, 7, 371-385).

In the case of an agonist, the AC50 is calculated by plotting the curve of the product at the concentration of the reference ligand giving 80% activation. The percentage activation which corresponds to the maximum level of activity obtained is also measured.

Materials and Method:

The HeLa cell lines used are stable transfectants containing the plasmids ERE-βGlob-Luc-SV-Neo (reporter gene) and RAR (α, β, γ) ER-DBO-puro. These cells are seeded into 96-well plates at a rate of 10,000 cells per well in 100 μl of DMEM medium without phenol red and supplemented with 10% defatted calf serum. The plates are then incubated at 37° C., 7% CO₂ for 4 hours.

The various dilutions of the test product, of the reference ligand

(4-(5,5-dimethyl-8-p-tolyl-5,6-dihydronaphthalen-2-ylethynyl)benzoic acid), of the 100% control (100 nM 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)propenyl]benzoic acid) and of the 0% control (500 nM 4-{(E)-3-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)]-3-oxopropenyl}benzoic acid) are added at a rate of 5 μl per well. The plates are then incubated for 18 hours at 37° C., 7% CO₂.

The culture medium is removed by turning the plates over, and 1.00 μl of a 1:1 PBS (phosphate buffered solution)/luciferin mixture are added to each well. After 5 minutes, the plates are read using the luminescence reader.

Results:

The values of the apparent Kd constants are indicated in the table below. These values are compared to those of the compounds of WO 99/10308 having the same activities.

RAR RAR RAR alpha beta gamma Kdapp Kdapp Kdapp (nM) (nM) (nM) Compound of Example 1 15 2 0.1 Compound of Example 2 60 15 0.5 Compounds of WO 99/10308: 3″-Methyl-2′-(5,5,8,8-tetramethyl- 2 1 0.25 5,6,7,8-tetrahydronaphthalen-2- yl)-[1,1′:4,1″]-tert-phenyl-4″- carboxylic acid (Example 41) 3″-Hydroxy-2′-(5,5,8,8- 2 1 0.25 tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)- [1,1′:4,1″]-tert-phenyl-4″- carboxylic acid (Example 46) 2″-Methoxy-2′-(5,5,8,8- 4 2 0.5 tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)- [1,1′:4,1″]-tert-phenyl-4″- carboxylic acid (Example 44) 2″-Hydroxy-2′-(5,5,8,8- 8 4 1 tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)- [1,1′:4,1″]-tert-phenyl-4″- carboxylic acid (Example 42) 6-[2-(5,5,8,8-Tetramethyl-5,6,7,8- 4 1 1 tetrahydronaphthalen-2- yl)biphenyl-4-yl]nicotinic acid (Example 47) 2′-(5,5,8,8-Tetramethyl-5,6,7,8- 2 1 1 tetrahydronaphthalen-2-yl)- [1,1′:4,1″]-tert-phenyl-4″- carboxylic acid (Example 14)

The results obtained with 4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid and 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid clearly show a better selectivity of these compounds for the RAR gamma receptor subtype in comparison with the other two subtypes RAR alpha and RAR beta. They also show a better activity and a better selectivity in comparison with the most active RAR compounds described in WO 99/10308.

These compounds are therefore selective agonists or activators of the RAR gamma receptor.

Example 4 Examples of Formulations

In this example, various specific formulations based on the compounds according to the invention are illustrated.

A - ORAL ADMINISTRATION: (a) Tablet of 0.2 g: 4′-(3-Hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.001 g tetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Starch 0.114 g Dicalcium phosphate 0.020 g Silica 0.020 g Lactose 0.030 g Talc 0.010 g Magnesium stearate 0.005 g (b) Oral suspension in 5 ml ampoules: 4′-(3-Hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.001 g tetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Glycerol 0.500 g 70% Sorbitol 0.500 g Sodium saccharinate 0.010 g Methyl para-hydroxybenzoate 0.040 g Flavoring qs Purified water qs 5 ml

B - PARENTERAL ADMINISTRATION: (a) Composition: 4′-(2,3-Dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.05% tetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Polyethylene glycol 20% 0.9% NaCl solution qs 100 (b) Injectable cyclodextrin composition: 4′-(2,3-Dihydroxypropyl)-3′-(5,5,8,8-tetramethyl- 0.1 mg 5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid β-Cyclodextrin 0.10 g Water for injectable preparation qs 10.00 g

C - TOPICAL ADMINISTRATION: Ointment: 4′-(3-Hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.300 g tetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Codex white petroleum jelly qs 100 g (b) Nonionic water-in-oil cream: 4′-(2,3-Dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.100 g tetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Mixture of emulsive lanolin alcohols, of waxes 39.900 g and of oils (“anhydrous eucerin” marketed by BDF) Methyl para-hydroxybenzoate 0.075 g Propyl para-hydroxybenzoate 0.075 g Sterile demineralized water qs 100 g (c) Lotion: 4′-(3-Hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.100 g tetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Polyethylene glycol (PEG 400) 69.900 g 95% Ethanol 30.000 g

Each patent, patent application, publication, text and literature article/report cited or indicated herein is hereby expressly incorporated by reference in its entirety.

While the invention has been described in terms of various specific and preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims, including equivalents thereof. 

1. A biphenyl compound of formula (I):

in which R is a hydrogen atom or a hydroxyl radical, and also the salts thereof.
 2. A compound as defined by claim 1, the same being 4′-(3-hydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid.
 3. A compound as defined by claim 1, the same being 4′-(2,3-dihydroxypropyl)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylic acid.
 4. A medicament comprising a compound as defined by claim
 1. 5. A pharmaceutical or cosmetic composition, which comprises, formulated into a pharmaceutically or cosmetically acceptable carrier, at least one compound of formula (I) as defined by claim
 1. 6. The pharmaceutical or cosmetic composition as defined by claim 5, formulated for topical administration.
 7. The pharmaceutical or cosmetic composition as defined by claim 5, wherein the amount of compound of formula (I) ranges from 0.001% to 3% by weight, relative to the total weight thereof.
 8. A regime or regimen for the prevention and/or treatment of pathologies linked to a deficiency of the activation of the RAR gamma receptor, comprising administering to an individual in need of such treatment, a thus effective amount of a compound of formula (I) as defined by claim
 1. 9. A regime or regimen for the treatment of a pathology linked to a cell differentiation and/or proliferation disorder, comprising administering to an individual in need of such treatment, a thus effective amount of a compound of formula (I) as defined by claim
 1. 10. A regime or regimen for the treatment of acne, comprising administering to an individual in need of such treatment, a thus effective amount of a compound of formula (I) as defined by claim
 1. 11. A regime or regimen for the treatment of psoriasis, comprising administering to an individual in need of such treatment, a thus effective amount of a compound of formula (I) as defined by claim
 1. 12. A regime or regimen for the treatment of a pathology linked to a keratinization disorder, comprising administering to an individual in need of such treatment, a thus effective amount of a compound of formula (I) as defined by claim
 1. 13. A process for preparing a compound of formula (I) as defined by claim 1, comprising the following steps: i) Suzuki reaction from the compound of formula 1

and the compound of formula 2

to produce the compound of formula 3

ii) reaction of the compound of formula 3 with triflic anhydride to produce the compound of formula 4

iii) reaction of the compound of formula 4 with allyl tri-n-butyl tin to produce the compound of formula 5

iv) hydration or dihydroxylation of the allylic double bond of the compound of formula 5 to produce the compound of formula 6 in which R is, respectively, a hydrogen or a hydroxyl radical

v) saponification of the ester function of the compound of formula
 6. 